Multi-center collaboration is necessary to begin to answer many of our most pressing questions in pediatric critical care medicine. The Collaborative Pediatric Critical Care Research Network (CPCCRN) has emerged as an effective model for addressing the hurdles facing multi-center investigators. We at Nationwide Children's Hospital (NCH) are exceptionally well positioned to become a part of the CPCCRN network. With a total of 60 critical care beds (40 pediatric, 20 cardiothoracic) and > 2,500 admissions annually, we are one of the largest critical care programs in the country. Our 19 full-time faculty enjoy remarkable access to research resources including critical care-specific research coordinators, data collectors, and biostatistical support. In addition we have in-PICU and Research Institute-based laboratory resources that permit around-the-clock sample collection and processing as well as provide cutting-edge biomarker and immune function quantitation services for the CPCCRN network. Under the leadership of Dr. Mark Hall, we offer the following: Global Specific Aim: To maximally participate in CPCCRN network studies with a goal of contributing meaningfully to the generation of new knowledge for the betterment of critically ill children. As part of this submission we present the concept proposal entitled, GM-CSF for Immunostimulation After NeuroTrauma (GIANT) study. The overall objective of this study is to demonstrate that treatment with the drug granulocyte-macrophage colony-stimulating factor (GM-CSF) can reduce the incidence of secondary infection in high-risk, children with severe traumatic brain injury (TBI) through restoration of immune function. The incidence of secondary infection and impairment of innate immune function are both common following critical injury, particularly neurotrauma. We have developed the capacity to perform highly standardized, generalizable, functional immune monitoring and our preliminary data show that critically injured patients with severe reduction immune function are at high risk for the development of secondary infection. Our experience with the FDA-approved drug GM-CSF is that it can reverse critical illness/injury-induced immune suppression. We are currently conducting an NIH-funded clinical dose-finding trial of GM-CSF in injured children, but its effect on infection risk remains unknown in children with severe TBI. We therefore propose a prospective, multi-center, randomized, double-blind, placebo controlled clinical trial of GM-CSF in children with severe TBI who are found to have severe innate immune suppression. Our central hypothesis that immunomodulation with GM-CSF will result in reduction in the risk of secondary infection after critical TBI in high-risk patients through safe, rapid, and sustained improvement in innate immune function. We will use an immunophenotype-driven approach to screen for the presence of severe innate immune suppression in the days immediately following injury. Subjects with severe immune suppression will be randomly assigned to receive GM-CSF or placebo in a blinded fashion. Immune function will be monitored serially and secondary infection will be investigated in response to specific clinical triggers. The incidence of new, nosocomially acquired infection will be compared between study groups over time. In addition, we will serially evaluate plasma cytokine levels and, when an external ventricular drain (EVD) is present, cerebrospinal fluid (CSF) cytokine levels to correlate the functional immune response to GM-CSF with levels of pro-inflammatory cytokines in the blood and the brain. Lastly, we will carry out serial, longitudinal neurodevelopmental testing modeled after the approach used successfully in the PECARN/CPCCRN THAPCA trials to test the null hypothesis that neurodevelopmental status will be no different between GM-CSF- and placebo-treated subjects. We anticipate that the GIANT study will represent a paradigm shift in the management of pediatric neurotrauma in that it will demonstrate the role of immune stimulation in safely reducing infection risk after critical injury, will show the feasibility of real-time immune functin monitoring, and will yield the largest and most comprehensive set of immune function data of any trauma population yet studied. We also firmly believe that Nationwide Children's Hospital will serve as an outstanding member of the Collaborative Pediatric Critical Care Research Network. This view is informed by our large and diverse patient population, our track record of single- and multi-center research, our unique portfolio of critical care-specific and general research resources, and the experience of our investigative team.